Near Allagash, the Saint John is joined by the Allagash River. The whole portion of the Saint John River that lies entirely in Maine is essentially a wilderness waterway, although many smoothly weathered granite boulders within the channel were broken by blasting during the early 20th century log driving.[5] Below St. Francis, the Saint John begins to form part of the international boundary between Maine and New Brunswick.

Further south at Woodstock, the river leaves the Upper Valley and turns east, heading away from the border region. It is joined by Nackawic Stream at Nackawic and passes small communities such as Bear Island. The Maliseet capital of Meductic was located along the Saint John River in the 17th and into the mid-18th century. This site was flooded in 1965 after completion of the Mactaquac Dam with the waterline level 133 feet (41 m) above sea level. The river continues eastward until it reaches New Brunswick's capital city Fredericton (where it becomes navigable, at an elevation of 6 feet (1.8 m) above sea level) and then the military town of Oromocto. Turning south from Oromocto, the river is joined by the short Jemseg River which empties New Brunswick's largest lake, Grand Lake. This part of the river valley becomes broad and shallow. The river is dotted by many low islands used for pastureland during dry periods in the summer and fall.

South of the Jemseg, the Saint John River is surrounded by the low hills of the St. Croix Highlands. It is joined by several lateral bays, including Belleisle Bay, the Nerepis River and the Kennebecasis River. The Saint John River finally discharges into the Bay of Fundy at the industrial city of Saint John. Near the river's mouth is the site of the Reversing Falls, caused by the high tides of the Bay of Fundy. These tides are the highest in the world and cause the river to reverse its flow twice a day in a narrow gorge in the city's centre.

The Saint John River has a maximum depth of 50 metres above the Mactaquac Dam.[citation needed]

Members of the Wolastoqiyuk Nation, known also as the Maliseet, whose lands and culture have been and still are centered on the Saint John River, have historically called the river Wolastoq, translating to "good and beautiful river". This early historic connection between the Maliseet people and the Saint John River is embodied in their native name itself, and as the Wolastoqiyuk name translates to mean the people of the Wolastoq, the very cultural identity of the Maliseet was deeply tied to the river. The Saint John River, with its islands, shorelines and tributaries, was the homeland of the Maliseet, and these places were marked with the graves of their ancestors, village campsites, and symbolic place-names and origin stories which were a testament to the long historic presence of the Maliseet people on the river.[6]

French colonists developed the lower river valley as an important part of their colony of Acadia. Acadian settlements along the lower river during the 17th and 18th centuries included Fort La Tour (Saint John) and Pointe Sainte-Anne (Fredericton).

In 1758, during the French and Indian War, the North American front of the Seven Years' War, Colonel Robert Monckton began the St. John River Campaign. The British burned the Acadian villages along the river, forcing the inhabitants to flee, or taking them prisoner prior to deportation. The entire area fell under English control after their capture of Fort Sainte-Anne in Fredericton at the end of the St. John River Campaign (1759).

The Royal Proclamation of 1763 had a direct impact on the Maliseet Nation along the Saint John River, or as it was first named by the indigenous peoples of the area, the Wəlastəkok. The proclamation stated that no British settlers could purchase lands belonging to the indigenous inhabitants. Land purchases could only be negotiated by the Crown. All the lands belonging to the "Indians", communities as well as hunting and fishing grounds, were to be left for their continued use.[7] The land on the Wəlastəkok was desirable to settlers, as it was a waterway connection between the Atlantic coast and Quebec, farming land, fishing grounds, and had mineral wealth. The proclamation did not stop settlers from obtaining the land they wanted. Organizations such as the St. John River Society were formed shortly after the proclamation was issued, in order to determine how to get around the new laws. Soon after, new survey maps were drafted, with First Nations deliberately left off, and many indigenous place names changed or Anglicized. By doing this, the land appeared empty, and now fell under a category of adopted Roman law called Terra Nullius. This law allows any unoccupied land to be taken over by the finder.

In her chapter from Shaping an Agenda for Atlantic Canada, Andrea Bear Nicholas writes, "With a map that represented the land as empty and two proclamations inviting English settlers to 'vacated' lands, Nova Scotia [included New Brunswick during this time] authorities began actively recruiting speculators and settlers to the region."[8]

In 1784, many Loyalist refugees from the American Revolutionary War were resettled in Saint John, Fredericton, and along the river at other settlements such as Queensbury and Woodstock. The arrival of the Loyalists was the catalyst for organization of the new British colony of New Brunswick. Saint John was named the capital, but it was moved to Fredericton some 60 miles (97 km) up river during the War of 1812 in fear of capture by the Americans. During that time a Martello tower was constructed to protect the Saint John harbour. British settlement of the fertile Upper River Valley did not take place until the early-to-mid-19th century. An immigrant Danish community (New Denmark) was established in the late 19th century.

In 1785, Acadians returning from the deportation settled in the Upper Saint John River valley, near what is now Edmundston. Somewhat later in the mid-19th century, francophone Quebecers also settled the Madwaska region, travelling southwards along traditional portage routes from the Saint Lawrence River valley. They joined the Acadians. The Madawaska section of the river valley is still strongly francophone in the 21st century.

The river was an important trade route for French, English and First Nations traders throughout the 17th and 18th centuries. The tremendous flow rate of the river and its tributaries during the spring freshet aided the development of the timber industry in western New Brunswick, and the river became a conduit for log drives to sawmills and pulp mills in the south. The spring freshet can prove disastrous to property owners along portions of the river, particularly when ice jams cause extensive flooding during the spring break-up.

Spring freshet and ice break up near Westfield on the Saint John River, 1936

With the development of lumbering and agricultural resources, the upper river valley area, by the 1820s and 1830s, became increasingly economically important. Both American and British citizens settled the area and, since the international boundary in this area was poorly defined, conflict between the British colony of New Brunswick and the state of Maine inevitably erupted. The Aroostook War developed when the respective state and colonial militias were called out. At the height of the tensions brought on by the Aroostook War, the positioning of the Maine militia on the Aroostook and Fish rivers while British troops were north and east of the Saint John River would eventually become the officially established boundary line between Maine and New Brunswick. During the boundary negotiations led by Lord Ashburton between 1839 and 1842, Maine wanted to retain the Aroostook River valley as well as the right to freely navigate the Saint John River. American surveyors had actually ventured up through a lot of the poorly drained land north of the Saint John River to realize its value was of little significance. A positive compromise that came out of the Aroostook war was the third article of the Webster–Ashburton Treaty which stated that navigation on the Saint John River would be completely free and open to both New Brunswick and Maine.[9] The border was ultimately defined by the Webster-Ashburton Treaty of 1842, but land disputes carried on for many years among settlers and lumbermen with legitimate claims.[10]

The Saint John River in the 19th century was integral to the development of western New Brunswick. As it had for thousands of years, it served as the principal transportation artery to the region, particularly prior to the era of rail transport, when paddle wheelers plied its waterways.

View of the railroad bridge at Woodstock looking south

New Brunswick industrialist Alexander Gibson commissioned a survey in 1866 for a railway line extending from his mill facilities in South Devon at the river junction with the Nashwaak River opposite Fredericton, north to Edmundston to service timber lands which he leased from the Crown. A charter for the railway was received from the provincial government in 1870, and the New Brunswick Land and Railway Company (NBR) was formed. Part of the charter provided for additional timber land based upon construction performance, thereby making Gibson one of the largest landowners in the province. Andrew George Blair, while Minister of Railways and Canals in the government of Wilfrid Laurier, was instrumental in forging the railway line further onwards to its junction with the rest of Canada in Quebec City. The entire NBR was sold in 1941 by Canadian Pacific Railways, which operated the railway in the first half of the 20th century, to forestry operator J. D. Irving Limited.

During the 1950s and 1960s, the river was developed as a major source of hydroelectric power with the construction of the Beechwood Dam in 1955 and the Mactaquac Dam in 1965. Large reservoirs were created behind the dams. These massive projects followed the construction of a smaller dam at Grand Falls in 1925, where the river descends in a steep cataract. Construction of the latter two dams has caused a severe decline in migrating Atlantic salmon, and resource authorities have developed fish ladders and other measures to try to revive the migration. In addition, much fertile farmland was flooded to create the headponds.

In recent years, the river has been a destination for recreational boating and ecotourism. The rich soil of the Upper Saint John River Valley in Carleton and Victoria counties in New Brunswick and Aroostook County in Maine continues to be cultivated for potatoes.

At the most upstream gauge the riverflow has ranged from 44,400 cubic feet per second (1,260 m3/s) to 59 cubic feet per second (1.7 m3/s). At the Dickey gauge flow has ranged from 91,700 cubic feet per second (2,600 m3/s) to 129 cubic feet per second (3.7 m3/s). At the Clair gauge flow has ranged from 151,000 cubic feet per second (4,300 m3/s) to 510 cubic feet per second (14 m3/s). Water flow is highest during the spring freshet and lowest in the fall. In early spring, upper sections of the river can experience ice jams causing flooding,[12] while in the lower sections in the broader floodplain, flooding may occur during late spring from the sheer volume of water which must make its way through the narrow gorge at the Reversing Falls.

The Building of the Bridge: An Idyl of the River Saint John written by Barry Straton is a poem that reflects on the bridge that was being built over the Saint John River in Fredericton in the 1880s.[13] The 19-page poem was published in 1887. The Fredericton Bridge was a wooden pedestrian and wagon bridge commissioned in 1884 in order to connect the growing the communities along the river. The region was flourishing in part due to the railway system. The bridge was completed the next year and officially opened on November 27, 1885.[14]

The last stanza on page 10 references the fears people had of the choice of building materials, wood rather than steel or concrete. Because of the regional climate, flooding can be extensive and bring large chunks of ice, washed away trees, and other debris at high speed. People were unsure if the wooden bridge would withstand the temperament of the river.

"Called from the eloquent solitudes
of fair New Brunswick's wealthy woods,
Tough birch, outlasting years of years,
shall form foundations for the piers.
Jointed and bolted, and hemmed around
By ponderous piles which pierce the ground,
And filled with anchoring tons of rocks,
Deep in the stream the stout cribs lie,
And stem the tide which rushes by
And bravely bear the ice-floe's shocks.
O, builders! lay them true and strong;
For if the humbler work go wrong
The finer parts ye rear in vain:
Even so the social life of a man,
Which national strength may ne'er attain..."[15]

Despite fears of the chosen building materials the bridge lasted 10 years, only failing after catching on fire and burning down.[16][17]